DESCRIPTION Adapted from the applicant's abstract): This proposal is based on the premise that after chromosomal rearrangements or other mutations disrupt its regulation, EVI1 is inappropriately expressed in CML cells and synergizes with the BCR/ABL pre-existing oncogene to give a highly proliferating and aggressive leukemic clone not responding to cytokines that control cellular growth or differentiation. By using a combination of molecular and biological assays, and by comparing the effects of EVI1 and MDS1/EVI1, it is proposed to identify the genes targeted by EVI1 and the mechanisms by which EVI1 inhibits IFNalpha-induced response. Finally, the applicant will begin a prospective study of CML patients to confirm that expression of EVI1 can be used as a prognostic marker for IFNalpha-therapy resistant patients. The ability to identify CML patients who will not respond to IFNalpha-therapy will be a very valuable clinical tool that could affect their treatment and their overall survival.